The present invention is directed toward a method and device for destroying unwanted fat cells by induction of programmed cell death (apoptosis). In particular it relates to a method and device that places substances such as Ultra Violet light (UV) and other chemical substances which induce programmed cell death (suicide cell self destruction) in direct contact with fat cells lying underneath the skin.
The desire of individuals to lose weight and specifically, to lose fatty tissue, has become nearly an obsession in the United States and many other countries. Any simple and safe method toward achieving a slim figure is in great demand. Methods for losing weight include hundreds of advised diets, machines and methods for exercise, various psychiatric techniques involving alteration in mental attitudes, and a variety of surgical techniques. Liposuction has created an entirely new surgical cosmetic industry, but carries a small but significant risk and often leaves the patient with an unsightly cosmetic result due to the inflammatory reaction surrounding where the fatty tissue has been removed by a technique which produces a severe tissue reaction.
Obesity is a serious public health hazard, second in importance only to tobacco. Approximately ⅓ of Americans are seriously overweight according to life insurance data. In approximately 12 million Americans, obesity significantly contributes toward the cause and complications of serious disease. Such conditions include heart and lung disease, many types of cancer, diabetes, high blood pressure, and peripheral arterial disease. This is in addition to how obesity becomes a cosmetic problem. Being overly fat limits both length of life and its quality.
A multi-billion dollar industry has developed in an effort to control weight. The many varied and expensive techniques employed speak to the relative ineffectiveness of the many techniques that have been tried to get rid of excess fat.
Obesity has recently been recognized as a public health hazard of epidemic proportions by the World Health Organization. One of three Americans between the ages of 20-74 are obese (Body Mass Index  greater than 30 Kg/m2 body surface). This amounts to 58 million people. The number of obese adults has increased dramatically. In 1980 25% of US adults were obese. The equivalent figure was 33% in 1990. In Europe the equivalent figure is about 40%.
Obesity significantly contributes to the dangers of other diseases in approximately half of those who exceed the threshold description of obesity. For example, 19% of the cost of management of heart disease can be ascribed to obesity. Obesity is also recognized as a co-morbid factor for obese patients suffering from degenerative arthritis, peripheral vascular disease, and many forms of pulmonary disease such as emphysema. The expenditure for products, goods, and services in the management of obesity is estimated to be $33 billion per year. This is 3%-4% of total health care expenditure per year and exceeds that expended for AIDS and cancer.
Obesity is such a prevalent, important and distressing problem that its many methods for suggested management are too well known to deserve more than listing. They include diets that exclude fats and high caloric elements, food supplements, appetite suppressants, exercise machines and regimes, biofeedback and other psychotherapeutic techniques, and a variety of operative techniques. Operations include a number of methods for decreasing the capacity the stomach, gastric by-pass operations, methods to shorten the small intestinal absorption surface, excision of the unwanted fat (lipectomy) and techniques of liposuction. Liposuction is performed approximately 51,000 times each year in the US. The maximum amount of fat that can safely be removed is approximately 2 Kg. Being an operative technique for removing fat, in this case by suction, it inevitably excites an inflammatory response at the operative site, which results not only in post operative inflammation but in subsequent uneven and unsightly scarring beneath the skin where the fat has been removed. Numerous patents involve devices and techniques of liposuction. For example, U.S. Pat. No. 5,527,273 to Manna et al. discloses an ultrasonic lipectomy probed; U.S. Pat. Nos. 5,642,270 and 5,644,585 to Mitchell et al. disclose the use of a yag laser to ablate tissue; and U.S. Pat. No. 5,143,063 to Fellner discloses the use of heat to non-invasively destroy adipose tissue. Such methods which destroy cells by heat, laser or ultrasound or by liposuction of direct trauma, are relatively crude in that they involve rough manipulation of body tissue fat cells and therefore incite severe local inflammatory reaction. This results in scarring and other immediate and longer term pathologic reactions. Such adverse reactions add to the probability of immediate complications (morbidity and sometimes even mortality) and to a poor subsequent cosmetic result at the site of the inflammatory response.
In every person hundreds of thousands of old or damaged cells die each day by the process of apoptosis and are replaced in the ebb and flow of maintaining a constant number of living cells in the body. Old and damaged cells die in response to a signal triggered on the cell surface for the targeted cell to self destruct (commit suicide). A popular synonym for this process is programmed cell death. Such cell turnover occurs without causing tissue reaction. Apoptosis is the body""s mechanism for cell disposal which maintains a balance between the removal of old cells and their replacement by new cells. Some cell types are quickly replaced. Others, including brain, nerve and to a lesser degree fat cells, lack in varying degrees the potential for self renewal. Fat cells promptly increase or decrease in individual cell size in response to overeating or diet, but have at best limited self renewal potential.
The signal triggering cell surface receptors that induce cell suicide are highly specific for each cell type. Within the past two decades there has been intense study of factors which stimulate apoptosis, particularly as they provide a potential for destruction of cancer cells. Each cell type has its own specific receptor which can be activated or blocked.
Cell self destruction by apoptosis must be differentiated from destruction by outside forces such as direct injury, infection, or heat-each of which produces cell destruction which results in cell necrosis and scarring. Apoptosis can be differentiated from necrosis by microscopic and specific chemical analytic methods. Necrosis results in the familiar signs of inflammation including swelling, redness, pain and tenderness. Apoptosis does not stimulate such reactions. The cells shrivel up, break into pieces and the contents are quietly removed by methods that do not induce inflammation.
Therefore, a need exists for a method and a device to eliminate undesirable adipose tissue in a safe, inexpensive and efficient manner without inciting violent local tissue reaction such as occurs following liposuction removal of fat cells, or by their destruction by heat, laser, ultrasound or other similar methods. There is also a need for a method and device that can destroy undesired fat cells by stimulating apoptotic events in fat cells, thus ridding a patient of undesired fat without the harmful reactions experienced by present fat-removal techniques and procedures.
The device and technique of the present invention does not incite the above described deleterious reactions. Instead, apoptosis is triggered by activation of a signal mechanism on the surface of a cell which commands the cell to self destruct. An important mechanism in apoptosis involves cutting off the energy supply to cell function. The present invention is a new method for ridding the body of excess unwanted body fat using a temporarily implanted device placed adjacent to the targeted fatty areas. The device delivers chemical or light signals to the fat cells to self destruct by a recognized physiologic pathway termed apoptosis. This is the mechanism by which the body ordinarily disposes of old or damaged cells, without inciting an inflammatory reaction.
The present invention provides a means by which depots of unwanted excess fat in the body can be stimulated to destroy themselves by. The present invention applies signals directly onto the surface of targeted unwanted fat cells to undergo such self destruction or apoptosis.
Apoptosis is like cutting off the gasoline supply to the cylinders of an automobile. It simply stops functioning. Cell damage by heat, laser, ultrasound or direct surgical trauma is like the damage from outside forces to the entire automobile. Cells made to commit suicide by apoptosis merely shrivel up and automatically decompose, inciting no inflammatory reaction and leaving no more trace than does atrophy of other aged or slowly dying tissue.
The device and method of the present invention induces programmed cell self-destruction (apoptosis) in unwanted fat cells by activating mechanisms on the surface of the cell which start a chain of reactions which prompt the cell to self destruct. Apoptosis is a relatively recently discovered mechanism by which cells of various types are induced to xe2x80x9ccommit suicidexe2x80x9d by specific mechanisms. The process is the one the body uses to remove aged or dying cells thousands of times every day as younger cells take their place. Apoptosis can be induced or inhibited by several signaling mechanisms. In general, a receptor on the surface of the cell serves as a switch which starts a series of subsequent signals within the confines of the cell which shortly thereafter stops the biochemical machinery which supports cell function, causing such cells to die. Apoptosis has been called the command which orders the cell to die by suicide. It apparently does so by blocking the energy mechanisms within the mitochondria situated within the cell. Cut off from its energy by apoptosis, the cell shrivels up and disintegrates in a fashion that can be identified on microscopic examination. Such apoptotic degeneration differs markedly from the appearance of cells killed by heat or other direct injury. Neither does it require the participation of immune responses from other defending cells within the body.
Each type of cell has a particular resistance or sensitivity to its own apoptotic signaling mechanism. Some cells, such as certain types of thymocytes (circulating white blood cells) are sensitive to UV radiation. Many other cells are more resistant. Like a specifically designed key, the apoptotic triggering mechanisms are usually uniquely designed for each cell type. The substances used for signaling fat self destruction are those found to be effective for fat cells.
The present invention introduces AIF (apoptosis inducing factors) directly onto the pad of fat that lies beneath the skin. The command for fat cell destruction is thus focused specifically on the fat cells intended for destruction. This is achieved by inserting an endoscope, such as is now commonly used for performing removal of diseased gall bladders or in so called minimal access repairs of inguinal hernia or in some patients requiring appendectomy. Such commercially manufactured endoscopes are used hundreds of thousands of times a year in various types of operations. They consist of small diameter plastic tubes, fitted with a light source and a tiny television camera at the tip which permit performance of operative procedures at the end of the scope under direct visions through another small caliber tube. Because their use requires only two or more very short (1-2 centimeter) skin incisions for their insertion, their use is referred to as minimal access surgery. The device of the present invention can be viewed as modified existing laparascopes so they deliver apoptosis inducing factors directly onto the fat cells located beneath the intact skin.
The present device is introduced through a small 1-2 cm skin incision. Once positioned beneath the skin, a plane is developed between the overlying layer of fat and the separated layer of fascia and underlying muscle. Using a technique now frequently used in minimal access inguinal hernia repair, the space is enlarged by use of a distending balloon which raises the skin and fat off the firm floor consisting of fascia and muscle. Only an infrequent small blood vessel transverses this space developed by the balloon. When bleeding occurs it can be stopped either by pressure or with an operating cautery. Most of the blood supply to the subcutaneous fat comes from the overlying skin, not from below. A wide subcutaneous space is thus created by the endoscope for deploying the AIF delivery system onto the overlying layers of fat. Although the technique above described develops a plane beneath the anterior abdominal wall, the same device can be used to approach fat located in other areas of the body, such as in the retroperitoneal space where fatty tumors often develop. The present invention delivers a signal for the targeted fat cell to self destruct without the harmful reaction of removal by ordinary operative or other types of injury. In one embodiment, because the device is temporarily left adjacent to the underside of the targeted fat, the apoptotic signal which triggers fat destruction can be repeated for as long as fat destruction is indicated. At the end of treatment the device is removed. The specific signals delivered are those proven to stimulate fat cells to self destruct and as delivered to this confined site are of proven safety to other tissues. Both chemical and special wave length light can be used, separately or in combination, as apoptotic signals.
In another embodiment of the present invention, a targeted stimulus to fat cell self destruction is achieved by transmitting the chemical or light source apoptosis stimulus from outside the body to the site of the unwanted fat through a short skin incision using plastic tubes for the admission of soluble chemical stimulants and fiberoptics for the transmission of light signals. The biologically unreactive tubes or fibers lead from outside the body through a tunnel beneath the skin and fat to the undersurface of the targeted fat. The signals which by-pass the skin, deliver the signals directly on to the unwanted fat. Because the device is made of and/or covered by biologically unreactive materials, it can be left in place for a prolonged period. This permits continued or pulsed delivery of the apoptosis signals to the targeted fat for as long as necessary to destroy the fat depot. When the desired amount of fat has been destroyed, the device can be removed by simple endoscopic surgical techniques.
Two general categories of apoptosis inducing factors (AIF) are used in the currently described technique: The first is Ultra Violet light (UV); the second consists of chemical substances proven to induce apoptosis of fat cells. UV is a well known component of sunlight. Under ordinary conditions the skin blocks UV light from substantially penetrating to the underlying fat. The present device by-passes the protective layer of skin overlying the pad of unwanted fat, and transmits the UV beam directly onto the targeted fat through an endoscope inserted a short distance from the target fat. The UV light is transmitted through the scope via fibers capable of transporting such light. The device thus flanks the protecting skin which ordinarily blocks the apoptotic inducing UV from contact with the mass of underlying fat cells. The suicide signal is thus delivered to the unwanted fat cells via the back door to the fat cells, despite the protective coat of the overlying skin.
Ultra violet light induces apoptosis in certain types of lymphocytes and in keratinocytes in the skin. The latter provide most of the protective function of the skin to underlying tissues. Red light (wave length 1 m to 760 nm) and Ultra violet light (wave length 760 nm to 180 nm) are known as non-ionizing radiation in contrast to X-rays which have a shorter wave length and have far more toxic potential. Both Ultra Violet (UV) and Infra Red (IR) light are used extensively in industry and in clinical practice. Safe levels of exposure to both UV and IR are defined by the American Conference of Governmental Industrial Hygenisists (ACGIH). Such limits are expressed in Threshold Limit Values (TLV) and Biological Exposure Index (BEI).
Both UV and Red and Infra red lasers are used extensively in clinical practice. Lasers are used to destroy targeted tissue by high energy highly focused beams of light of a single and congruent wave length focused on tissues that are targeted for destruction. Their most common use is to destroy tumor tissue or to burn highly focused holes in the atherosclerotic plaques that plug up small blood vessels (endarterectomy). Such high energy beams are in direct contrast to the low energy exposure in the embodiment in which necrosis is avoided and the targeted cell is induced to undergo self destruction by apoptosis. Knowledge of laser generation and transmission can be utilized for delivering much less intense beams into the body in the embodiment.
IR can be generated from Light Emitting Diodes using minute amounts of electricity. This is the familiar source of red or white lights on the dashboard of an automobile, or the ON-OFF signal on a toaster or microwave oven, wrist watch or computer. IR is transmitted by many types of fiberoptics. Skin effectively blocks transmission of most of the sun light to the fat and other underlying tissues.
By the use of fiberoptics, one embodiment of the present invention takes UV or other light from an extracorporeal source and transmits it directly to the under surface of fat beneath the skin. The fibers run from the emitting source outside the body through a small incision in the skin remote from the targeted fat area, through a subcutaneous tunnel to the undersurface of the targeted fat.
In one embodiment as pictured in FIG. 4, an endoscope is inserted into the space in the right lower quadrant to provide visualization of the space as the device is being positioned as it emerges from the tube in the right upper quadrant. The port on the patient""s left provides access of a forceps manipulated by an assistant in positioning of the device. In another embodiment (FIG. 8), the delivery tubes lie on top of the pad; a suction catheter for removal of freed fat and dead cell debris lies at the base and beneath the pad on which the tubes are anchored.
The UV or IR light apoptosis stimulants are generated outside the body, transmitted by special fiberoptics, led into the body through a small skin incision into an endoscopically created tunnel to the surface of the targeted fat, where the light beams are concentrated on the targeted fat. An underlying impenetrable biologically unreactive plastic skirt protects the underlying fascia and muscle from the light exposure.
In other embodiments of the present device and technique, agents in solution or suspension that are known to induce fat cell apoptosis are delivered directly onto the surface of unwanted fat cells via the uniquely designed endoscope of the present invention. Some such substances activate (or block) triggering mechanisms on the surface of the targeted cell. Others alter the molecular configuration or orientation of the surface cell receptors. Still others seem to work by stimulating or blocking the messengers that run from the cell surface to the packages of energy (mitochondria) within the wall substance. The end result often is disintegration of the DNA within the nucleus of the cell, which shortly thereafter causes cell disintegration.
The chemical apoptosis stimulants used in the present invention are those proven effective in provoking fat cells self destruction. The fluid conveying the stimulant to the fat cell serves to irrigate and by a suction catheter to remove the damaged and dying fat cells. A wide underlying protective plastic skirt and a suction catheter protects the underlying fascia and muscle from significant influence of the apoptotic stimulant.
An extraordinary variety of molecules are of proven effectiveness in triggering apoptosis in specific cell types. Each cell type has its unique stimulating molecule which like a key in a lock fits its cell surface receptor which sends a self destructive signal to the nucleus or the mitochondria to self destruct, including but not limited to those set forth in 4) Korsmeyer, SJ in Trends in Genetics, Vol II, No 3, 101-105, March 1995. The mitochondria is the power source for cell metabolism. When the energy source is interrupted, metabolism stops and the cell disintegrates.
Certain uniquely designed embodiments of the present device permit extension of the delivery time of the AIF. At its simplest, the AIF, whether UV or a chemical substance, can be delivered all at one time while the scope is in place immediately below and in contact with the fat cells. This requires precise control of the dose schedule so it will remove only the precise amount of fat desired. Alternative embodiments involve leaving the delivery system in place beneath the overlying pad of fat, so that if the first administration of the AIF has not resulted in sufficient fat cell apoptosis, additional administrations of AIF can be delivered. One of skill in the art will appreciate the dosages and administration regimens required to affect layers of fat in a fashion to remove such fat from a patient""s body. by induction of fat cell apoptosis, and in particular is directed to a method and device that delivers a chemical or light signal to fat cells to cause such cells to self-destruct.
The effects of both chemical apoptosis stimulants and light stimulants can be enhanced by special procedures, such as changing the chemical environment of the target fat, or when light stimulants are used, for example, by staining the fat with dyes which enhance the effects of the transmitted light.